MDM2

protein-coding

MDM2 proto-oncogene, the group of Ring finger proteins|Zinc fingers RANBP2-type

Gene summary

This gene encodes a nuclear-localized E3 ubiquitin ligase. The encoded protein can promote tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. This gene is itself transcriptionally-regulated by p53. Overexpression or amplification of this locus is detected in a variety of different cancers. There is a pseudogene for this gene on chromosome 2. Alternative splicing results in a multitude of transcript variants, many of which may be expressed only in tumor cells. [provided by RefSeq, Jun 2013]

MANE transcript

NM_002392.6

Inheritance

AR, AD

ClinVar variants

U:108B:35

Top phenotype

Lessel-Kubisch syndrome

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr12:68,808,177-68,845,544

External References & Databases

Ensembl (ENSG00000135679)

Transcript & Mutation Effects

hg38 • Region Span ~37.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lessel-kubisch syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032868

Submitter: Labcorp Genetics (formerly Invitae)

lessel-kubisch syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032868

Submitter: PanelApp Australia

Li-Fraumeni syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018875

Submitter: Orphanet

lessel-kubisch syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032868

Submitter: LiferaOmics

Genetic evidence – Published PMID: 28846075 – Reports one molecularly confirmed affected individual from a consanguineous family with segmental progeroid phenotype consistent with Lessel–Kubisch syndrome. Family 1 – one proband. Case-level (AR pLOF; homozygous; scored once; consanguinity −0.5 applied) = 1.0; segregation = 0 (two reportedly affected sisters and a first-cousin relationship in the pedigree, but no DNA available; not scorable); case-control = 0; Family 1 total = 1.0. PMID: 39504961 – Reports one affected individual. Case-level (non-LOF start 1.0; homozygous; consanguinity unknown so no deduction applied) = 0.1; segregation = 0; case-control = 0; Family 2 total = 0.1. Published genetic evidence total = 1.0+0.1= 1.1 / 12 Genetic evidence – Our cases Family 1 – One proband. Case-level (AR LOF-supported allele; homozygous; consanguinity −0.5 applied) = 1.0; segregation = 0 (siblings clinically unaffected; no genotyping performed); case-control = 0; Family 1 total = 1.0. Our cases total = 1.0 / 12 Total genetic evidence (published + our cases) 1.1 + 1.0 = 2.1 / 12 Experimental evidence – Published PMID: 28846075 – Functional studies demonstrate defective p53 degradation and increased stability of mutant MDM2 in patient fibroblasts and engineered cells. Zebrafish embryos deficient in mdm2 display a severe apoptotic phenotype rescued by wildtype but not mutant mdm2 mRNA, supporting a functional loss-of-function mechanism consistent with disease biology. Functional alteration (patient cells) = 2.0; Functional alteration (engineered cells) = 1.0; Model / rescue (zebrafish non-rescue) = 2.0; Experimental evidence total = 5.0 / 6 Overall score Genetic evidence = 2.1 Experimental evidence = 5.0 Overall score = 7.1 / 18

Clinical Genomic Database (CGD)

Lessel-Kubisch syndromeAR

Manifestation: Craniofacial; Dermatologic; Endocrine; Renal

Intervention: Renal

Rationale: Among other features, the condition may involve renal failure associated with severe hypertension, and awareness may allow early diagnosis and management

Refs: 28846075

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MDM2 variants in ClinVar

5 Conditions Cataloged

Accelerated tumor formation, susceptibility toTotal: 172

not specifiedTotal: 27

Lessel-kubisch syndromeTotal: 11

not providedTotal: 3

MDM2-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002392.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	32 clinvar	1 clinvar	36
missense			100 clinvar	2 clinvar		102
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	108	34	1	143

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002392.6	RefSeq	NP_002383.2	11	MANE Select
ENST00000258149.11	Ensembl	ENSP00000258149.6	11	MANE Select
NM_001145337.3	RefSeq	NP_001138809.1	10	Standard
NM_001145339.2	RefSeq	NP_001138811.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mdm2	Danio rerio	Structure: renal capsular space Quality: dilated abnormal

Gene / Model

Organism

Observed Phenotype

mdm2

Danio rerio

Structure: renal capsular space

Quality: dilated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Chronic myeloid leukemia - Homo sapiens (human)
Melanoma - Homo sapiens (human)
Bladder cancer - Homo sapiens (human)
Cell cycle - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
blood vessel development
blood vessel remodeling
regulation of heart rate
atrioventricular valve morphogenesis

Molecular Function

p53 binding
ubiquitin-protein transferase activity
protein binding
5S rRNA binding
zinc ion binding

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000462284
Coding exons: 11
Length: 37259
Individuals with no LoFs: 124791
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 124794
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.33	150	255	0.589	0.0000119	3288
Missense (PolyPhen)		76	148.5	0.51178		1912
Synonymous	0.596	81	88.1	0.919	0.00000424	880
Loss of Function	4.81	1	28.9	0.0346	0.00000148	359

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). {ECO:0000250|UniProtKB:P23804, ECO:0000269|PubMed:12821780, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:15632057, ECO:0000269|PubMed:16337594, ECO:0000269|PubMed:17290220, ECO:0000269|PubMed:19098711, ECO:0000269|PubMed:19219073, ECO:0000269|PubMed:19837670, ECO:0000269|PubMed:19965871, ECO:0000269|PubMed:20173098, ECO:0000269|PubMed:20385133, ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:22128911}.;
Disease: DISEASE: Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.;

Recessive Scores

pRec: 0.640

Intolerance Scores

LoFtool: 0.317
RVIS EVS: -0.52
RVIS percentile EVS: 21.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium